This project includes investigation of molecular aspects of rabies virus infection in cell culture, characterization of the pathogenesis and the immune response associated with rabies infection in experimental mammals, and further studies designed to develop improved methods for vaccination of man. The primary objective of molecular biological studies is the determination of the mechanisms of viral RNA transcription and replication, particularly with respect to the contribution of requisite cell nuclear factors to be characterized by parallel studies of normal and enucleated cells. Studies in experimental animals will be designed to answer the unresolved questions: 1) How does rabies virus kill? 2) How does virus persist during lengthy incubation periods and non-fatal infections? 3) Why does immunity sometimes accelerate the fatal course of rabies infection? and 4) How may post-exposure vaccination induce protection? The components of the immune and interferon response, the neurophysiological disease, the role of defective interfering viruses, and the gross and electron microscopic pathology of rabies infection will be studied. Further attempts will be made to improve human diploid cell vaccine for human use, to develop more effective means of administering the vaccine post-exposure, and to develop more valid tests for assessing vaccine efficacy.